Pharmaceutical compositions containing 2,2,5,5-tetrakis(polyfluoromethyl) imidazolidines and imidazolines and methods of using such

ABSTRACT

DESCRIBED AND CLAIMED ARE PHARMACEUTICAL COMPOSITIONS CONTAINING PSYCHOTROPIC OR MUSCLE-RELAXANT 2,2,5,5TETRAKIS(POLYFLUOROMETHYL)IMIDAZODILINES AND IMIDAZOLINES OF MY COPENDING SER. NO. 521,317, AND THE USE OF THE PHARMACEUTICAL COMPOSITIONS.

United States Patent O PHARMACEUTICAL COMPOSITIONS CONTAIN- ING2,2,5,5-TETRAKIS(POLYFLUOROMETHYL) IMIDAZOLIDINES AND IMIDAZOLINES ANDMETHODS OF USING SUCH William J. Middleton, Wilmington, Del., assignorto E. I. du Pont de Nemours and Company, Wilmington, Del. No Drawing.Division of application Ser. No. 521,317,

Feb. 9, 1966, now Patent No. 3,459,766, which is a continuation-in-partof application Ser. No. 461,151, June 3, 1965, which in turn is acontinuation-in-part of application Ser. No. 439,476, Mar. 12, 1965.This application Apr. 17, 1969, Ser. No. 817,201

Int. Cl. A61k 27/00 U.S. Cl. 424-473 18 Claims ABSTRACT OF THEDISCLOSURE Described and claimed are pharmaceutical compositionscontaining psychotropic or muscle-relaxant 2,2,5,5-tetrakis(polyfluoromethyl)imidazodilines and imidazolines of mycopending Ser. No. 521,317, and the use of the pharmaceuticalcompositions.

RELATED APPLICATIONS This application is a division of my copendingapplication S.N. 521,317 filed Feb. 9, 1966, now U.S. Pat. No.3,459,766, which itself is a continuation-in-part of my application S.N.461,151 filed June 3, 1965, now abandoned, and which in turn was acontinuation-in-part of my application S.N. 439,476 filed Mar. 12, 1965,now abandoned.

BACKGROUND OF THE INVENTION Field of the invention This inventionrelates to, and has as its principal objects provision of, novelpharmaceutical compositions and their use.

Prior art My copending application Ser. No. 521,317, of which this is adivision, discloses novel compounds which are the 4-imino 2,2,5 ,5tetrakis(polyhalomethyl)irnidazolidines, their isomeric or tautomericforms, the 4-amino- 2,2,5,5 tetrakis(polyhalomethyl)-3-imidazolines, andselected derivatives of the same. Formulas for these compounds whereinany halogen is chlorine or fluorine can be written as:

Imidazolidine Form II. Imidazoline Form wherein:

(A) R is hydrogen or alkyl; (B) X is selected from the group consistingof:

C(CF NH hydrogen; alkyl; benzyl, carbethoxymethyl; lower alkenyl;dimethylaminoethyl; lower alkynyl; cyclohexyl; cyclohexenyl; lower alkylsubstituted with 1 halogen or 1 lower alkoxy;

3,567,831 Patented Mar. 2, 1971 ice hydroxymethyl; hydroxymethoxymethyl;N-pyrrolidylmethyl; N piperidylmethyl; N morpholinylmethyl; ordimethylaminomethyl;

where Q is lower alkyl; cyclohexyl; or

2)2 s)2 and (C) Z, Z Z and Z alike or difierent, are selected from thegroup consisting of hydrogen and fluorine; and (D) with the proviso thatR and X together are of no more than 30 carbons.

Compounds of the above structure in which R is H and X and Z are aspreviously defined are tautomers, and existing tautomeric equilibrium,especially in solution, as

As would be expected from this tautomeric equilibrium involving a mobileproton, these compounds have marked acidic properties. For example, thishydrogen will exchange rapidly with deuterium when D O is added to anacetone solution of the compound, as evidenced by the disappearance ofthe NH absorption band in the nuclear magnetic resonance spectrum.

In the special case of4-imino-2,2,5,5-tetrakis(trifluoromethyl)imidazolidine and4-amino-2,2,5,5-tetrakis(trifluoromethyl)-3-imidazoline in which both Rand X are H, and all Zs are P, these two hydrogens exchange with eachother so rapidly that only a single absorption band is observed at 25 C.from these protons in the N.M.R. spectrum; and they both exchangerapidly with D 0. As a practical matter these two tautomers normallyexist together so that when one or the other is mentioned it isunderstood that the mixture of the two is included.

Since compounds of types I and II in which R is H exhibit acidicproperties, they can form salts with bases. The salts from the twotautomers are identical, for their anions can be represented by thefollowing resonance forms corresponding to the tautomeric forms of typesI and H.

For example, 4 imino-2,2,5,5-tetrakis(trifiuoromethyl)- imidazolidine isa weak acid. It can be titrated with a strong base, such astetramethylammonium hydroxide, in a nonaqueous solvent such as pyridine,to give a sharp end-point. The salt formed in this titration can berepresented by the resonance structures:

4 acetylimino 2,2,5,5 tetrakis(trifluoromethyl) imidazolidine (R=H, X=CHCO, and all Zs=F) is a stronger acid. It can be titrated in water withsodium hydroxide to give a salt that can be represented by the resonancestructures:

Compounds of the above general formula in which neither R nor X is Hexist as isomeric structures similar to types I and II above. Either oneor both types of these compounds can be prepared in a single reaction bycausing a tautomeric mixture, in which R is H or R and X both are H, toreact with an alkylating or acylating reagent. For example, a dimethylderivative corresponding to type I (R and X=CH and a dimethyl derivativecorresponding to type II (R=X=CH and all ZszF) can be prepared in asingle reaction by treating 4-imino- 2,2,5,5 tetrakis(trifiuoromethyl)imidazolidine with dimethyl sulfate.

Solid complexes may be formed from the compounds of this invention withsolid or liquid complexing agents, Difunctional complexing agents suchas diethyl oxalate, dimethyl malonate, diacetyl and benzil have beenfound most effective, but simpler compounds such as diethyl carbonatealso form weak complexes. These complexes are usually isolated in a 1 to1 molar ratio of compound to complexing agent, even if a molar excess ofone of the materials is present. For example, a 1 to 1 complex, dec.8285 C., is formed if4-imino-2,2,5,5-tetrakis-(trifluoromethyl)imidazolidine isrecrystallized from an ether-pentane solution containing an excess ofdiethyl oxalate. The stability of a complex depends on the specificcompound and complexing agent involved. Frequently the complexes tend todecompose or dissociate when heated or put into solution. The abovementioned thermal instability is usually evidenced by a wide meltingrange. Usually these complexes may be considered as single mixtures orsolvates of the compound with complexing agent, and they are usuallyeffective in the same applications as the parent compound.

Compounds in which R or X contain an amino moiety will form salts withacids such as hydrogen chloride, acetic acid, and the like, and withalkyl halides such as methyl iodide. Such salts are usually morewater-soluble than the compounds from which they are derived but havethe same general utilities. For the pharmacological purposes of theinvention, it will be understood that the acids or bases used to formsalts are to be pharmacologically acceptable.

The compounds are biologically active and cause striking pharmacologicaleffects therapeutically useful in the treatment of neurological andpsychiatric disorders. Thus, they exert depressant effect upon thecentral nervous system, decreasing skeletal muscle tone, a desirableproperty for treatment of hypertonic or hyperkinetic motor disorders.This property is also useful in causing relaxation in generalanesthesia.

Preferred central nervous system depressants include those compounds inthe above-defined active group in which any alkyl substituent contains14 carbon atoms; any aryl, aralkyl or alkaryl substituent contains 6-8carbon atoms; and any hydrocarbyloxycarbonyl substituent contains 1-13carbon atoms.

This invention comprises pharmaceutical compositions containing theabove-identified compounds.

DESCRIPTION OF THE INVENTION Those compounds of my application Ser. No.521,317 in which all halogen is chlorine or fluorine have psychotropicactivity or are good muscle-relaxants and can be employed as such inwarm-blooded animals. Tests for such pharmacological activities aredescribed as follows:

An excellent method for demonstrating muscle-relaxant activity is theuse of the 30 Inclined Screen Test of L. O. Randall et al. [J. Pharm.Exp. Therap., 129, 163 (1960)]. This test determines the dose whichcauses 50% of the test animals (mice) to lose their footing on a wiremesh which is inclined 30 from the horizontal. This is called theparalyzing dose or PD value. In this test, low PD values indicate highpotencies.

Another method for demonstrating muscle-relaxant activity is the WireLift Test. The forefeet of albino mice are placed on a taut wirestretched at a level of approximately 12 inches over a flat surface.Normal animals grasp the wire and lift their hind feet to the wire,where balance is maintained. Inability to lift the hind legs to the wireis taken as a positive response and is considered to be a measure ofmuscle relaxation. This test determines the dose which imparts to 50% ofthe test animals (mice) an inability to lift their hind legs to thewire, and which is called the effective dose or ED value. Dose responserelationships and the calculation of PD and ED values were determined bythe method of L. C. Miller and M. L. Tainter, Proc. Soc., Exp. Biol.Med. 57, 261-264 (1944).

An excellent method for demonstrating psychotropic (antipsychotic,antineurotic, antianxiety) activity is the Conditioned AvoidanceResponse Test in rats (R. Clark A Rapidly Acquired Avoidance Response inRats, Psychonomic Science, 1966, 6 (1), 1112). The animals are trainedto avoid an electric shock to the feet by moving through a hole in apartition in response to a warning signal (light and sound) whichprecedes shock onset by 10 seconds. This test determines the dose whichprevents 50% of the rats from avoiding the electric shock.

This is called the Avoidance Failure ED value. In this test low EDvalues indicate high potencies.

Another method for demonstrating psychotropic activity is theExploratory Activity Test in mice. For this test, mice are individuallyplaced on a stainless steel wire mesh screen (8" x 12", 3 mesh per inch,A mesh, supported 1" above a laboratory bench) and observed for normalalert investigative activities, such as olfactory movements of the nose,head movements with apparent visual examination of the area and/orwalking around on the screen. Normal mice will make these responseswithin 2 to 3 seconds. Absence or a marked depression of this activitywithin seconds (particularly of the first 2 components) is consideredloss of explora tory activity. This test determines the dose whichcauses a loss of exploratory activity in 50% of the mice. This is calledthe Exploratory Loss ED value. In this test low ED values indicate highpotencies.

EMBODIMENTS OF THE INVENTION There follow some non-limiting exampleswhich illustrate the invention in detail.

Examples l27.-A number of tests were made, forming the examples of thisapplication, in which compounds of application Ser. No. 521,317 wereadministered to mice to determine the PD and ED dosage values. As iswell known in pharmacology, each series of toxicological data was takento include at least one dose low enough so that all subjects survive andone dose high enough that none survive. Amounts between these twoextremes were also taken and from the observed test results it ispossible to calculate the PD and ED value by a graphic technique wellknown in pharmacology, that is, the method of Miller and Tainterreferred to above. This method was used in obtaining the dosage valueslisted in the table which follows.

In the test system, the compounds were administered in single doses togroups of 5 to 10 mice at each of 4 or 5 dosage levels. The test animalswere observed for the effects indicated at various time intervalsranging from 15 minutes to 24 hours after dosing. The doses wereselected so as to bracket the P D or the ED value in degree of effect.The highest dose tested generally produced a maximal or near maximaleffect. The lowest dose tested generally produced a minimal effect. AllPD and ED values were determined at the time of peak effect for eachcompound. The compounds were prepared as solutions or suspensions ineither an aqueous polyvinyl alcohol, gum acacia vehicle or an aqueousmethylcellulose vehicle and administered at 10 to 25 milliliters perkilogram of animal body weight. All the compounds were given orallyexcept for the Exploratory Activity Test in which test the compoundswere given by intraperitoneal injection of an oil solution of thecompound. Oral administration was accomplished by intubation, that is,by placing the desired dosage in aqueous medium in a syringe to which ashort length of rubber tubing is attached and inserting the free end ofthe tube into the mouth of the test animal and down to the stomach. Thedosage was then expelled from the syringe directly into the stomachthrough the tubing. The results of the tests are given as examples inthe following table.

TABLE I.RESULTS OF TESTS FOR MUSCLE RELAXANT AND PSYCHOTROPIO ACTIVITYInclined Explor. Avoidance screen Wire lift loss failure PD50 EDso ED50EDao Compound (mg/kg.) (mg/kg.) (mg/kg.) (mg/kg.)

Example:

1 4-inlilianoi2,2,5,5-tetrakis(trifluoro-methyl)imidazolidine 10. 65:0.9 7. 05:0. 51 12 1. 5

2 4-imino-2,5-bis(diflu0romethyD-2,5-bis(trifluoromethyl) 17.35:1.3 10.05:0. 83 7 3.0

imidazolidine (5 3 4-imino-3-methyl-2,2,5,5-tetrakis(trifluoromethyl)20. 511. 7 13. 05:1.3 20 3. 5

imidazolidine (7). 43-methyl-4methylimino-2,2,5,5-tetrakis(trifluoromethyl) 30. 05:3.3 19.55:2.3 20 2.8

imidazolidine 5 3-ethy1-4-imino-2,2,5,fi-tetrakis(trifluoromethyl) 17.05:1.4 12. 35:1. 0 20 imidazolidine (8 64-dimethylamino-2,2,5,5-tetrakis(trifluoromethyD-3- 20.0 20

imidazoline (9 7 3-ethyl-4-ethylimino-2,2,5,S-tetrakis(trifluoromethyl)57. 0i14.0 30. 05:3. 9 100 imidazolidine (10). 84-ethylamino-2,2,5,5-tetrakis (trifiuoromethyD-S- 17. 55:24 8. :0. 75 12imidazoline (10). 93-ethyl-4-methylimino-2,2,5,5-tetrakis(trifluoromethyl) 30. 013.3 20

imidazolidine (11). 104-ethylimino-3-methyl-2,2,5,5-tetrakis(trifluoromethyl) 22. Oil. 6 36imidazolidine (12). 11 4-benzylamin0-2,2,5,5-tetrakis(trifluoromethyD-3-45. 0:b7. 6 30. 05:54 36 imidazoline (13). 124allylamino-2,2,5,5-tetrakis(trifiuoromethyD-B- 41. 05:4.8 28. 05:3.0 608. 6

imidazoline 13 4-methylamino-2,2,5,5-tetrakis(trifluoromethyD-3- 18.85:1.3 10. 85:0. 86 12 2.1

imidazoline (16). 144hydroxymethylamin0-2,2,5,5-tetrakis(trifluoromethyl) 13. 25:1. 6 5.65:0. 85 12 4.0

imitiazoline (20). 15 4-hydroxymethoxymethylamino-2,2,5,5-tetrakis 16.Oil. 3 7. fiiLO 12 (trifiuoromethyl)-3-imidazoline (21). 164-(N-pyrrolidylmethylamino)-2,2,5,5-tetrakis(trillnoro- 18. 85:1. 7 10.55:0. 7 12 methyD-B-imidazoline hydrochloride (23). 174-dimethylaminomethylaminofl,2,5,5-tetrakis(trifluoro- 22. 05:1.810.05:1 1 12 methyD-3-imidazoline (26). 184-dimethylaminomethylamin02,2,5,5-tet1'akis(tiifiuoro- 19.2i1. 2 7.5i1.2 7

methyll-B-imidazoline hydrochloride (27). 194-afieylin1rasa-2,2,5,5-tetrakis-(trifiuommethyDimidaz- 24. 05:19 13.:1. 1 12 4.0

0 me 20 Tetramethylarnmonium salt of 4-acetyl-imiuo-2,2,5,5-tetra- 16.Oil. 6 8. 85:1. 03 12 kis(trifluoromethyl)-imidazolidine (31) 214-chloroacetylimin0-2,2,5,5-tetrakis(tiifluoromethyl) 16. :14 9. 85:0.77 7 imidazolidine (32). 224-acetylimino-3-methyl-2,2,5,5-tetrakis(tiiflnoromethyl) 24. 0i2. 5 15.05:0. 85 4. 0

imidazolidine (34). 234-(heptanoylimino)-2,2,5,fi-tetrakis-(trifluoromethyl) 28.55:2.910.055). 6 20 imidaiolidine (30). 244%carbethoxyimino)-2,2,5,5-tetrakis(trifluoromethyl) 14.55-1. 4 10. 210.87 7 imidazolidine (43). 25 4(carbomethoxyimino)-2,2,5,5-tetrakis(tritluoromethyl) 17.051. 011.55:1.1 7 2,9

imidazolidine (44). 264-(Z-dimethylaminoethoxycarbonyl-imino)-2,2,5,5-tetrakis 33. 55:3.2 19.25:1.9 20

(trifluorom ethyDimidazolidine (45). 274-N-pyrrolidy1methylamino-2,5-bis(difiuoromethyl)-2,5-bis- 30 7. :1. 1 7

1 The numbers in parentheses after the names of the compounds are thenumbers of the examples in which the compound is described in mycopending application Serial No. 521,317.

2 Not available.

While the preceding examples show the use of intubation and parenteralinjection, it is understood the compounds can be administered to aliving body by all methods known in pharmacy and medicine. They can begiven orally in capsules, elixirs, syrups and the like and parenterallyin solution in suitable liquid carriers. The dosage will vary and willdepend on such factors as the condition being treated; age and weight ofthe recipient; the responsiveness of the recipient; prior, concurrentand intended subsequent medication and treatment; general health of therecipient, frequency of treatment; and of course the nature of theeffect desired.

Generally speaking, the active compound will be administered in apharmacologically beneficial amount. Administration can be in a singledose or in a plurality of doses over an extended period of time. It willof course also be understood that in a course of treatment, an initialdose can be in greater amounts if appropriate to obtain a rapidresponse. Thereafter the minimally effective dosage, or maintenancedosage, is determined.

A single dose will rarely exceed about 10 to 20 milligrams of activecompound per kilogram within this invention, although larger amounts canbe used as called for in any given situation. Extremely small doses willeffect some benefit but as a practical matter a single dose of less thanabout 0.001 to 0.002 milligram per kilogram will seldom be used.Ordinarily, doses will range from 0.05 to 10 mg./kg. and preferably 0.05to mg./kg. Doses can be repeated in the same or greater or lesseramounts over a period of time as long as improvement in the recipient isobserved or as long as needed under the circumstances.

The compound will ordinarily be administered with a nontoxicpharmaceutical carrier in a variety of practical dosage forms. Thesedosage forms are novel compositions comprising the nontoxicpharmaceutical carrier and a physiologically beneficial amount of theactive compound.

Suitable nontoxic pharmaceutical carriers or vehicles include liquidssuch as Water, aromatic water, alcohols, syrups, elixirs, pharmaceuticalmucilages, such as those containing acacia and tragacanth, oils ofpetroleum, animal, vegetable or synthetic origin, for example peanutoil, soybean oil, fish oil such as cod liver oil, or the like, for oraladministration; water, saline, aqueous lactose, aqueous maltose, aqueousglucose (dextrose), aqueous sucrose, fixed oils, and the like, foradministration by injection. Suitable solid carriers include softgelatin capsules, hard gelatin capsules, slow or delayed release pillsor capsules, powders, tablets, and the like. Suitable solid or liquidnontoxic pharmaceutical carriers are well known in the art and theselection of carrier can be from those appropriate and available inaccordance with well-known prescription techniques. The compositions ofthis invention therefore include such dosage forms as solutions,suspensions, syrups, elixirs, tablets, capsules, powder packets, and thelike.

A vast number of suitable pharmaceutical carriers are described inRemingtons Pharmaceutical Sciences by E. W. Martin, a well-knownreference text in this field.

In these novel compositions the new active compounds of this inventionwill be present in a pharmacologically beneficial amount as mentionedabove. In practice, this means that the active ingredient willordinarily constitute at least about 0.001% by Weight based on the totalweight of the composition. For oral administration in liquid medium suchas an elixir, the concentration will ordinarily be in the range fromabout 0.01-2.0% by weight of active ingredient. For injectablecompositions concentrations from 0.0050.5% are satisfactory. In tablets,powders, capsules and the like, the amount of active ingredient may, ifdesired, be as much as to 50% or more by weight of the totalcomposition. For oral administration as a solution in oil in a softgelatin capsule, concentrations of 0.05% to 10% by weight of activeingredient and 99.05% to 90% by Weight of a pharma- 8 ceuticallyacceptable oil will ordinarily suffice. The preferred concentrationswill be 0.2% to 5% by weight of active ingredient and 99.8% to by weightof the oil.

The active compounds of this invention can be formulated, if desired,with one or more pharmaceutically active materials for combinationeifects, treatments and benefits. Such materials include but are by nomeans limited to antidepressants or stimulants, vitamins, analgesics,tranquilizers, antibiotics, antitussive agents, etc. The compositionscan, of course, contain suitable pharmaceutical modifiers such ascoloring agents, sweetening or other flavoring agents, solubilizingagents, etc., as will readily occur to persons skilled in this art.

The following further examples and embodiments illustrate specificpharmaceutical compositions for administration to a living body:

Example 28.4 imino 2,2,5,5 tetrakis(trifiuoromethyl)imidazolidine isformulated conveniently in 20% by volume ethyl alcohol USP-water in 0.05by weight concentration for oral administration, with and without aflavoring agent, and a coloring agent, etc.; and in 0.05, 1, 5, 10 and25 milligram amounts in standard two-piece hard gelatin capsules with adiluent such as starch, mannitol or lactose, for oral administration. Inpharmacologic applications it is administered in these dosage forms atdosage levels in the range of 0.5 to milligrams, as described above.

Similar formulations are made with 4-imino-3-methyl- 2,2,5,5tetrakis(trifluoromethyl)imidazolidine and 3- ethyl 4 imino 2,2,5,5tetrakis(trifiuoromethyl)imidazolidine.

Example 29.4 imino 2,2,5,5 tetrakis(trifiuoromethyl)imidaz0lidine can beformulated for oral administration with suitable tableting adjuvantsusing a conventional tableting machine with the active ingredientconstituting 150% by weight of the tablet. Other ingredients includegelatin, magnesium stearate, and starch or mannitol as described in theforegoing Martin reference.

Formulations of the type illustrated by Example 29 are also made withany of the active solid compounds of this invention.

Example 30.4 amino 2,2,5,5 tetrakis(trifiuoromethyl)-3-imidazoline canbe formulated for oral administration in a soft gelatin capsule. Eachcapsule contains the following ingredients:

Mg. (1) Active ingredient 5.0 (2) Soybean oil, refined 212.0 (3) Gelatin74.190 (4) Glycerin 36.167 (5) Water 7.117 (6) Methylparaben 0.297 (7)Propylparaben 0.074 (8) FD&C Yellow No. 5 0.122 (9) Titanium dioxide0.541

The active ingredient is dissolved in soybean oil at C., the solution iscooled and injected by means of a positive displacement pump into thegelatin (which contains the other ingredients) to form the capsule. Thecapsules are washed in petroleum ether and dried.

The concentration of active ingredient in oil can be varied to provideother dosage strengths. Other pharmaceutically acceptable oils can beused such as: peanut oil, cottonseed oil, corn oil and the like.

Example 31.4 amino 2,2,5,5 tetrakis(trifiuoromethyl)-3-imidazoline canbe formulated for intramuscular injection by dissolving the compound incorn oil or sesame oil in concentrations of 0.1% to 1% (wt./vol.). Inaddition, 2 to 3% by volume of benzylalcohol, NF. may be included in thesolution. The solution is clarified by filtration, placed in glassampoules, sealed, and then sterilized by heating to C.

Example 32.No. 5 two-piece hard gelatin capsules for oral use can befilled with 110 mg. of a mixture consisting of 1.0 mg. of4-imino-2,2,5,5-tetrakis(trifiuoromethyl)imidazolidine, 0.2 mg. of thefinely divided, fumed silicon dioxide known commercially as Cab-O-Siland approximately 109 mg. of lactose.

Any of the active compounds of this invention can be used informulations of the type illustrated by Example 32.

Example 33.-A flavored elixir containing 1 mg. of 4- imino-2,2,5,5tetrakis(trifluoromethyl)imidazolidine in every ml. can be prepared bydissolving the compound in a flavored solution of sorbitol containing upto 50% of ethyl alcohol USP so that the final concentration is 0.02%weight/volume.

The disclosure herein should not be taken as a recommendation to use thedisclosed invention in any way without full compliance with US. Food andDrug Laws and other laws and governmental regulations which may beapplicable.

Since obvious modifications and equivalents in the invention will beevident to those skilled in the chemical and pharmaceutical arts, Ipropose to be bound solely by the appended claims.

The embodiments of the invention in which an exclusive property ofprivilege is claimed are defined as follows:

1. A pharmaceutical composition containing an effective amount ofpsychotropic or muscle-relaxant compound selected from the groupconsisting of:

(A) R is hydrogen or alkyl; (B) X is selected from the group consistingof:

-C(CF NH hydrogen; alkyl; benzyl, carbethoxymethyl; lower alkenyl;dimethylaminoethyl; lower alkynyl; cyclohexyl; cyclohexenyl; lower alkylsubstituted with 1 halogen or 1 lower alk- Y; hydroxymethyl;hydroxymethoxymethyl; N-pyrrolidylmethyl; N-piperidylmethyl;N-morpholinylmethyl; or dimethylaminomethyl;

where Q is alkyl; lower alkyl substituted with up to 3 halogens or 1lower alkoxy; phenyl; phenyl substituted with up to 3 halogen, 2 loweralkyl, 1 lower alkoxy, 1 amino or 1 lower alkyl-' substituted amino;2,4-dichlorophenoxymethyl; lower alkenyl; naphthyl; or amino(loweralkyl) or alkyl-substituted amino(lower alkyl) where the substituentsare alkyl of 1-4 carbons and where Q is lower alkyl; cyclohexyl; or

2)z a)2 and (C) Z, Z Z and Z alike or different, are selected from thegroup consisting of hydrogen and fluorine; and (-D) with the provisosthat R and X together are of no more than 30 carbons and any halogen ischlorine or fluorine; and a nontoxic pharmaceutical carrier therefor.

2. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4-amino- 2,2,5,5tetrakis(trifluoromethyl)-3-imidazoline, its tautomer 4imino-2,2,5,5-tetrakis(trifluoromethyl)imidazolidine, and mixturesthereof.

3. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4-imino- 3-rnethyl-2,2,5 ,5 -tetrakis(trifiuoromethyl imidazolidine.

4. A pharmaceutical composition of claim 1 wherein the phychotropic ormuscle-relaxant compound is 3-methyl-4-methylimino 2,2,5,5tetrakis(trifluoromethyl)imidazolidine.

5. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 3-ethyl-4-imino-2,2,5,5-tetrakis(trifluoromethyl)imidazolidine.

6. A pharamaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4-imino- 2,5-bis(difluoromethyl 2,5bis(trifluoromethyl)imidazolidine.

7. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4- methylamino 2,2,5,5tetrakis(trifluoromethyl)-3-imidazoline.

8. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4-benzylamino 2,2,5,5tetrakis(trifluoromethyl)-3-imidazoline.

9. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4-ally1-amino-2,2,5,5-tetrakis(trifluoromethyl)-3-imidazoline.

10. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4-acetylimino-3-methyl 2,2,5,5tetrakis(trifluoromethyl)imidazoline.

11. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4-hydroxymethylamino 2,2,5,5tetrakis(trifluoromethyl)-3- imidazoline.

12. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4-(chloroacetylimino) 2,2,5,5tetrakis(trifluoromethyDimidazolidine.

13. A pharmaceutical composiiton of claim 1 wherein the phychotropic ormuscle-relaxant compound is 4-(carbethoxyimino) 2,2,5,5tetrakis(trifluoromethylimidazolidine.

14. A pharmaceutical composition of claim 1 wherein the psychotropic ormuscle-relaxant compound is 4-(carbomethoxyirnino) 2,2,5,5tetrakis(trifiuoromethyl)imidazolidine.

15. A pharmaceutical composition for oral administration consisting of asoft elastic capsule containing a clear solution of an effective amountof a compound of claim 1 in a pharmaceutically acceptable oil.

16. A pharmaceutical composition for oral administration consisting of asoft elastic capsule containing a clear solution of an effective amountof a compound of claim 2 in a pharmaceutical acceptable oil.

17. A method of inducing a psychotropic effect or muscle relaxationcomprising administering to a living warm blooded animal an effectiveamount of a composition of claim 1.

18. A method of inducing a psychotropic effect or muscle relaxationcomprising administering to a living warm blooded animal an effectiveamount of a composition of claim 2.

References Cited UNITED STATES PATENTS 2,915,528 12/1959 =Raifsnider260309.6 3,310,570 3/1967 Middleton 260-299 STANLEY I. FRIEDMAN, PrimaryExaminer U.S. Cl. X.R. 424-24'8, 267

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,567,831 Dated March 2, 197].

Inventor(s) William J. Middleton It is certified that error appears inthe above-identified pater and that said Letters Patent are herebycorrected as shown below:

r. Col. line 30, "existing" should read exist in I Col. 9, line 30, thestructural formula should be Signed and sealed this 7th day of September1971 (SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHLAK Attesting Officer ActingCommissioner of Pa

